Infectious diseases are caused by pathogens such as bacteria and viruses and eukaryotic organisms ranging from single-celled fungi and protozoa, through large complex metazoan such as parasitic worms. Pathogenic bacteria may contain virulence factors that mediate interactions with the host, eliciting particular responses from the host cells that promote the replication and spread of the pathogen. Viruses rely on subverting the machinery of the host cell to produce their proteins and to replicate their genomes. Pathogens often colonize the host by adhering to or invading the epithelial surfaces that are in direct contact with the environment. Viruses rely largely on receptor-mediated endocytosis for host cell entry, while bacteria exploit cell adhesion and phagocytic pathways (1). Pathogenic fungi, protozoa and other eukaryotic parasites typically pass through several different forms during the course of infection; the ability to switch among these forms is usually required for the parasites to be able to survive in a host and cause disease.
During the initial hours and days of host exposure to a new pathogen, the innate immune system is the first line of defense against invading pathogens. However, the initiation of specific adaptive immune responses is also required. Innate immune responses rely on the body's ability to recognize conserved features of pathogens that are not present in the uninfected host. These include many types of molecules on microbial surfaces and the double-stranded RNA of some viruses. Surface molecules of microorganisms also activate the complement system to target these organisms for phagocytosis by macrophages and neutrophils, and to produce an inflammatory response.
Bacteria have developed different strategies to escape from phagocytes. For instance, they can inhibit chemotaxis and phagocytosis, kill or colonize the phagocytes. The phagocytic cells use a combination of degrading enzymes, anti-microbial peptides and reactive oxygen species to kill the invading microorganisms (2). In addition, they release signaling molecules that trigger an inflammatory response and begin to marshal the forces of the adaptive immune system. Bacteria, on the other hand, have developed different strategies directed against the adaptive immune system such as molecular mimicry, suppression of antibodies, hiding inside cells, or release of antigen into the bloodstream (3).
Intracellular pathogens, including all viruses and many bacteria and protozoa, replicate inside a host cell, which they invade by one of a variety of mechanisms. Viruses rely largely on receptor-mediated endocytosis for host cell entry, while bacteria exploit cell adhesion and phagocytic pathways. Protozoa employ unique invasion strategies that usually require significant metabolic expense. Once inside, intracellular pathogens seek out a niche that is favorable for their replication, frequently altering host cell membrane traffic and exploiting the cytoskeleton for intracellular movement.
Staphylococcus aureus is a microorganism frequently associated with bacterial arthritis, which results in synovial inflammation, cartilage and bone destruction, and eventually joint deformity. Various animal species including mammals, birds and reptiles have been observed to develop spontaneous S. aureus arthritis and are therefore potential models for the induction of the disease.
The plasminogen activator (PA) system is a general proteolytic system that has been suggested to play an important role in the development of different types of arthritis. Plasminogen can be activated to the broad-spectrum protease plasmin by either of the two physiological PAs, tissue-type PA (tPA) or urokinase-type PA (uPA).
Otitis media is defined as inflammatory conditions of the ear. Otitis media is the most common childhood disease except for the common cold. The most important etiological factor related to otitis media is bacterial or viral infections of the upper respiratory tract. Otitis media is generally benign and a self-limiting disease, but despite this, the prescription rate of antibiotics is high. In fact, effects of antibiotics in curing otitis media lack evidence and so far surgical intervention is the therapy of choice for the treatment of recurrent acute otitis media (AOM) and chronic otitis media or otitis media with effusion (OME).
It is well known that the immediate colonization by the patient's normal skin flora (i.g. S. aureus and Streptococcus pyogenes) occurs following injury. Especially after the introduction of penicillin G in the early 1950s, which resulted in the virtual elimination of Streptococcus pyogenes as a cause of infection in thermally injured patients, S. aureus became the principal etiological agent of wound infection. Therefore S. aureus is one of the most common bacterium species on open-wound infection. Incisional wounds and burn wounds are the most common wound types observed in clinical practice.
Antibiotics and other antimicrobial drugs have been widely used in treatment of infectious diseases since the World War II era. The success of antimicrobials against disease-causing microbes is among modern medicine's great achievements. However, many antimicrobials are not as effective as they used to be due to the development of drug resistance. A key factor in the development of antibiotic resistance is the ability of infectious organisms to adapt quickly to new environmental conditions. Over time, some bacteria have developed ways to circumvent the effects of antibiotics. Widespread use of antibiotics is thought to have spurred evolutionarily adaptations that enable bacteria to survive these powerful drugs. Antimicrobial resistance provides a survival benefit to microbes and makes it harder to eliminate infections from the body. Ultimately, the increasing difficulty in fighting off microbes leads to an increased risk of acquiring infections in a hospital or other setting. Diseases such as tuberculosis, gonorrhea, malaria, and childhood car infections are now more difficult to treat than they were just a few years ago. Drug resistance is an especially difficult problem for hospitals harboring critically ill patients who are less able to fight off infections without the help of antibiotics. Heavy use of antibiotics in these patients selects for changes in bacteria that bring about drug resistance. Unfortunately, this worsens the problem by producing bacteria with a greater ability to survive even in the presence of the strongest antibiotics. These even stronger drug-resistant bacteria continue to prey on vulnerable hospital patients. Therefore, there is an increasing awareness that novel therapeutical strategies are highly needed to improve the infection defense against infection.
Necrosis is the name given to unprogrammed or accidental death of cells and living tissue. It is less orderly than apoptosis, which are part of programmed cell death. In contrast to apoptosis, cleanup of cell debris resulting from necrosis by phagocytes of the immune system is generally more difficult, as the disorderly death generally does not send “eat-me” cell signals which tell nearby phagocytes to engulf the dying cell. This lack of signaling makes it harder for the immune system to locate and recycle dead cells which have died through necrosis than if the cell had undergone apoptosis. The release of intracellular content after cellular membrane damage is the cause of inflammation in necrosis.
There are many causes of necrosis including injury, infection, cancer, infarction, invenomation and inflammation. Severe damage to one essential system in the cell leads to secondary damage to other systems, a so-called “cascade of effects”. Necrosis is caused by special enzymes that are released by lysosomes which are capable of digesting cell components or the entire cell itself. The injuries received by the cell may compromise the lysosome membrane, or may set off an unorganized chain reaction which causes the release in enzymes. Unlike in apoptosis, cells that die by necrosis may release harmful chemicals that damage other cells. Biopsy material necrosis is halted by fixation or freezing.
Currently there are four major therapeutical methods to cure necrosis. The first is surgical removal, which is the most rapid, and therefore is recommended when large necrotic areas or thick eschar present. The second is mechanical removal, which includes hydrotherapy, dextranomers and wound irrigation. The third is enzymatic removal 1, the enzyme used is mainly collagenase (eg: Santyl), however, the effect is too slow when infection presents; and fourthly is through autolytic method, which is via enzymes in wound fluid but the effect is extremely slow. However, none of the four treatment methods provide a functional and aesthetically satisfactory necrosis removal and tissue remodeling. Therefore, a novel therapeutic strategy is in great need in order to achieve a successful removal of necrosis.
Current therapeutic methods for treating infections such as bacterial arthritis, open wound infection, otitis media and necrosis have drawbacks as discussed above. Therefore, there is a great need in the art for improved strategies for treating infections in general.